Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability
Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability
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DOI：
10.1016/s0092-8674(02)00762-6
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发表时间：
2002-06-14
期刊：
影响因子：
64.5
通讯作者：
Fisher, DE
中科院分区：
文献类型：
--
作者：
McGill, GG;Horstmann, M;Fisher, DE
KIT/SCF信号和MITF依赖的转录对黑素细胞的发育和色素沉着都是必不可少的。为了确定MITF依赖的Kit在原代黑素细胞中的转录靶点，进行了基因芯片研究。已确定的靶点是BCL2，它的种系缺失会导致黑素细胞丢失，并在小鼠身上显示出与MITF的表型协同作用。在黑素细胞和黑色素瘤细胞中，通过bcl2启动子的染色质免疫沉淀证实了MITF对bcl2‘S的调节作用。MITF还调节破骨细胞中的BCL2，MITF(mi/mi)和bcl2(-/-)小鼠都表现出严重的骨化症。MITF在黑素细胞或黑色素瘤中的破坏引发了深刻的细胞凋亡，容易被bcl2过表达所挽救。临床上，原代人类黑色素瘤表达微阵列显示MITF和BCL2紧密的近邻连锁。这种联系有助于解释MITF和Bcl2在黑素细胞谱系和众所周知的黑色素瘤治疗耐药中的重要作用。
Kit/SCF signaling and Mitf-dependent transcription are both essential for melanocyte development and pigmentation. To identify Mitf-dependent Kit transcriptional targets in primary melanocytes, microarray studies were undertaken. Among identified targets was BCL2, whose germline deletion produces melanocyte loss and which exhibited phenotypic synergy with Mitf in mice. BCL2's regulation by Mitf was verified in melanocytes and melanoma cells and by chromatin immunoprecipitation of the BCL2 promoter. Mitf also regulates BCL2 in osteoclasts, and both Mitf(mi/mi) and Bcl2(-/-) mice exhibit severe osteopetrosis. Disruption of Mitf in melanocytes or melanoma triggered profound apoptosis susceptible to rescue by BCL2 overexpression. Clinically, primary human melanoma expression microarrays revealed tight nearest neighbor linkage for MITF and BCL2. This linkage helps explain the vital roles of both Mitf and Bcl2 in the melanocyte lineage and the well-known treatment resistance of melanoma.